Tribrissen 400 Oral Paste Caution

Description

TRIBRISSEN Oral Paste is a combination of trimethoprim and sulfadiazine in the ratio of 1 part to 5 parts by weight, which provides effective antibacterial activity against a wide range of bacterial infections in animals.

Trimethoprim is 2,4 diamino-5-(3,4,5-trimethoxybenzyl) pyrimidine.

ACTIONS:Microbiology: Trimethoprim blocks bacterial production of tetrahydrofolic acid from dihydrofolic acid by binding to and reversibly inhibiting the enzyme dihydrofolate reductase.

Sulfadiazine, in common with other sulfonamides, inhibits bacterial synthesis of dihydrofolic acid by competing with para-aminobenzoic acid.

TRIBRISSEN Oral Paste thus imposes a sequential double blockade on bacterial metabolism. This deprives bacteria of nucleic acids and proteins essential for survival and multiplication, and produces a high level of antibacterial activity which is usually bactericidal.

Although both sulfadiazine and trimethoprim are antifolate, neither affects the folate metabolism of animals. The reasons are: animals do not synthesize folic acid and cannot, therefore, be directly affected by sulfadiazine; and although animals must reduce their dietary folic acid to tetrahydrofolic acid, trimethoprim does not affect this reduction because its affinity for dihydrofolate reductase of mammals is significantly less than that for the corresponding bacterial enzyme.

TRIBRISSEN Oral Paste is active against a wide spectrum of bacterial pathogens, both gram-positive and gram-negative. The following in vitro data are available, but their clinical significance is unknown. In general, species of the following genera are sensitive to TRIBRISSEN Oral Paste:

As a result of the sequential double blockade of the metabolism of susceptible organisms by trimethoprim and sulfadiazine, the minimum inhibitory concentration (MIC) of TRIBRISSEN Oral Paste is markedly less than that of either of the components used separately. Many strains of bacteria that are not susceptible to one of the components are susceptible to TRIBRISSEN Oral Paste.

A synergistic effect between trimethoprim and sulfadiazine in combination has been shown experimentally both in vitro and in vivo (in dogs).

TRIBRISSEN Oral Paste is bactericidal against susceptible strains and is often effective against sulfonamide-resistant organisms. In vitro sulfadiazine is usually only bacteriostatic.

The precise in vitro MIC of the combination varies with the ratio of the drugs present, but action of TRIBRISSEN Oral Paste occurs over a wide range of ratios with an increase in the concentration of one of its components compensating for a decrease in the other. It is usual, however, to determine MICs using a constant ratio of 1 part trimethoprim in 20 parts of the combination.

The following table shows MICs, using the above ratio, of bacteria which were susceptible to both trimethoprim (TMP) and sulfadiazine (SDZ). The organisms are those most commonly involved in conditions for which TRIBRISSEN Oral Paste is indicated:

AVERAGE MINIMUM INHIBITORY CONCENTRATION (MIC-mcg/mL)

Bacteria

TMP
Alone

SDZ
Alone

TMP/SDZ

TMP

SDZ

Escherichia coli

0.31

26.5

0.07

1.31

Proteus species

1.3

24.5

0.15

2.85

Staphylococcus aureus

0.6

17.6

0.13

2.47

Pasteurella species

0.06

20.1

0.03

0.56

Salmonella species

0.15

61.0

0.05

0.95

β Streptococcus

0.5

24.5

0.15

2.85

The following table demonstrates the marked effect of the trimethoprim and sulfadiazine combination against sulfadiazine-resistant strains of normally susceptible organisms:

Susceptibility Testing: In testing susceptibility to TRIBRISSEN Oral Paste, it is essential that the medium used does not contain significant amounts of interfering substances which can bypass the metabolic blocking action, eg, thymidine or thymine.

The standard SxT disc is appropriate for testing by the disc diffusion method.

Pharmacology: Following oral administration, TRIBRISSEN Oral Paste is rapidly absorbed and widely distributed throughout body tissues. Concentrations of trimethoprim are usually higher in tissues than in the blood. The levels of trimethoprim are high in the lungs, kidney, and liver, as would be expected from its physical properties.

Usually, the concentration of an antibacterial in the blood and the in vitro MIC of the infecting organism indicate an appropriate period between doses of a drug. This does not hold entirely for TRIBRISSEN Oral Paste because trimethoprim, in contrast to sulfadiazine, localizes in tissues and therefore, its concentration and ratio to sulfadiazine are higher there than in blood.

The following table shows the average serum concentrations of trimethoprim and sulfadiazine in 11 adult horses observed on Day 3 of three consecutive daily doses of TRIBRISSEN 400 Oral Paste:

AVERAGE SERUM CONCENTRATION (mcg/mL)

Trimethoprim (5 mg/kg)

Sulfadiazine (25 mg/kg)

1 hr

3 hr

6 hr

10 hr

24 hr

1 hr

3 hr

6 hr

10 hr

24 hr

0.71

0.95

0.37

0.04

<0.04

8.0

15.8

9.9

5.6

0.6

Excretion of TRIBRISSEN Oral Paste is chiefly by the kidneys, by both glomerular filtration and tubular secretion. Urine concentrations of both trimethoprim and sulfadiazine are severalfold higher than blood concentrations. Neither trimethoprim nor sulfadiazine interferes with the excretion pattern of the other.

Precautions

Water should be readily available to horses receiving sulfonamide therapy.

ANIMAL SAFETY: Toxicity is low. The acute toxicity (LD50) of TRIBRISSEN Oral Paste is more than 5 g/kg orally in rats and mice. No significant changes were recorded in rats given doses of 600 mg/kg per day for 90 days.

Horses treated intravenously with TRIBRISSEN 48% Injection have tolerated up to five times the recommended daily dose for 7 days or on the recommended daily dose for 21 consecutive days without clinical effects or histopathological changes.

Lengthening of clotting time was seen in some of the horses on high or prolonged dosing in one of two trials. The effect, which may have been related to a resolving infection, was not seen in a second similar trial.

Slight to moderate reductions in hematopoietic activity following high, prolonged dosage in several species have been recorded. This is usually reversible by folinic acid (leucovorin) administration or by stopping the drug. During long-term treatment of horses, periodic platelet counts and white and red blood cell counts are advisable.

TERATOLOGY: The effect of TRIBRISSEN 400 Oral Paste on pregnancy has not been determined. Studies to date show there is no detrimental effect on stallion spermatogenesis with or following the recommended dose of TRIBRISSEN 400 Oral Paste.

Dosage and Administration

The recommended dose is 3.75 g TRIBRISSEN 400 Oral Paste per 110 lbs (50 kg) body weight per day. Administer orally once a day by means of the Dial-A-Dose®* syringe. Each marking on the syringe doses 110 lbs (50 kg) body weight. When administering TRIBRISSEN 400 Oral Paste, the oral cavity should be empty. Deposit paste on back of tongue by depressing plunger that has been previously set to deliver the correct dose.

The usual course of treatment is a single, daily dose for 5 to 7 days.

Continue acute infection therapy for 2 or 3 days after clinical signs have subsided.

If no improvement of acute infections is seen in 3 to 5 days, reevaluate the diagnosis.

TRIBRISSEN 400 Oral Paste may be used alone or in conjunction with intravenous dosing. Following treatment with TRIBRISSEN 48% Injection, therapy can be maintained using oral paste.

A complete blood count should be done periodically in patients receiving TRIBRISSEN Oral Paste for prolonged periods. If significant reduction in the count of any formed blood element is noted, treatment with TRIBRISSEN Oral Paste should be discontinued.

STORAGE: Store at 15°-30°C (59°-86°F).

HOW SUPPLED: TRIBRISSEN 400 Oral Paste is available in 37.5 g Dial-A-Dose®* syringes.

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